The most resistant form of tuberculosis (TB), extensively drug resistant tuberculosis (XDR-TB) is defined as resistance to Isoniazid, rifampin, fluoroquinolones and one of three injectable second-line anti-TB agents. Drug-resistant TB arises when poor adherence leads to treatment failure. It has also been shown that drug-resistant TB may be acquired directly where such strains are endemic particularly in the setting of high prevalence of HIV infection. The public health threat of XDR-TB was highlighted in 2006 when an outbreak of XDR-TB among 58 HIV co-infected patients in KwaZulu-Natal, South Africa resulted in 100% mortality rate and a median survival of 16 days after diagnosis. Incidence of XDR has increased dramatically in KwaZulu-Natal province (KZN) over the past 3 years with the number of XDR-TB patients being referred for therapy doubling annually. While there have been retrospective studies of XDR-TB, there are currently no prospective studies of XDR-TB treatment and there are no treatment studies of XDR-TB and HIV co-infection. The proposed study is a prospective cohort study of treatment outcomes and epidemiologic risk factors among XDR-TB patients at a TB referral hospital in South Africa, the majority of whom are also HIV infected. While the study will continue for 3 years this project proposal concerns data which will have been gathered in the first year of the study. Specific aims include determining the effect of HIV co-infection on 2, 4, and 6 month TB culture conversion rates, effect of low CD4 count on culture conversion, type and incidence of adverse drug reactions, and the association of drug resistance mutations with treatment outcomes. While all analysis will take place at Boston University Medical Center (BUMC), the cohort will be recruited at King George V Hospital in South Africa. This study is a result of an ongoing collaboration between researchers at BU with researchers at the Centre for AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal. Funding for the study is through CAPRISA and a grant from the Potts Memorial Foundation. PUBLIC HEALTH RELEVANCE: This study may have important public health implications for treatment of drug resistant TB. The prevalence of MDR-TB and XDR-TB are rapidly increasing globally and HIV/XDR-TB co-infection represents a cartastrophe for both HIV and TB control. Characterizing variables associated with XDR-TB culture conversion, interactions with HIV co-infection, and incidence, severity and type of adverse drug interactions are important steps in optimizing treatment for this important public health challenge.